Process for the synthesis of beta-lactam derivatives

ABSTRACT

The invention is directed towards a process for the preparation of Cefuroxime acid or for a corresponding pharmaceutically acceptable salt or ester. The process comprises the carbamoylation of a Cefuroxime precursor with an activated isocyanate. Additionally, the process is characterized by the fact that a carbonic C1-C4 alkyl ester is used as a solvent for the carbamoylation reaction.

The invention relates to a process for the synthesis of Cefuroxime acid(I), i.e. (6R, 7R)-7-[[2-furanyl(sin-methoxyimino)acetyl]amino]-3-carbamoyloxymethylceph-3-em-4-carboxylic)acid, and the salts thereof, starting from 3-hydroxymethylceph-3-emprecursors with activated isocyanates in carbonic acid esters.

Cefuroxime is a cephalosporin widely used in the treatment of bacterialinfections thanks to its effective, broad spectrum antibacterialactivity against gram-negative bacterials, in particular in thetreatment of immunodepressed patients.

The acid product is the precursor both of the corresponding sodium salt,for the injection administration, and of the corresponding 1-acetyloxyester (Cefuroxime axetil), for the oral administration.

Said molecules are valuable in that they are highly resistant toβ-lactamases due to the methoxyimino group present in the side chain atthe 7- position of the cephalosporanic ring.

As far as the carbamoylation step of the 3-hydroxymethylceph-3-emprecursors is concerned, the known synthetic routes for the preparationof Cefuroxime make use of solvents, which involves potential risksconnected with their inflammability and toxicity. The method disclosedin U.S. Pat. No. 3,966,717 comprises the conversion ofdiphenylmethyl-3-hydroxymethyl-7β-(thien-2-yl)acetamidoceph-3-em-4-carboxylate into the corresponding3-carbamoyloxymethyl derivative by reaction withtrichloroacetylisocyanate in acetone and subsequent hydrolysis.

On the other hand, the synthesis disclosed in U.S. Pat. No. 4,284,767comprises the reaction of (6R,7R)-7-[[2-furanyl(sin-methoxyimino)acetyl]amino]-3-hydroxymethylceph-3-em-4-carboxylicacid with dichlorophosphinylisocyanate in tetrahydrofuran and thesubsequent recovery of the product in the form of the sodium salt.

Finally the synthesis described in U.S. Pat. No. 4,775,750 comprises theconversion of the same intermediate by reaction in methyl or ethylacetate with chlorosulfonyl isocyanate.

It has now surprisingly been found that Cefuroxime 3-hydroxymethylprecursors can be carbamoylated by reaction with activated isocyanates,using carbonic acid C₁-C₄ esters, preferably dimethylcarbonate anddiethylcarbonate, as reaction solvents. The risks involved by the use ofsaid solvents are remarkably lower than those connected with the use ofthe solvents cited above. Furthermore, said alkyl carbonates haveremarkably lower toxicity than the solvents reported above, THF, alkylacetates and acetone.

It should be pointed out that said reaction with isocyanates, which areextremely aggressive reactants, in solvents such as alkyl carbonates,has never before been reported in literature.

In the following table, the various solvents cited above are compared.The reported data are those of the respective safety requirementsreported on MSDS (Material Safety Data Sheet)—OHS.

TABLE Flash point oral DL50 rat (° C.) (mg/Kg) Acetone −18.0 5800Tetrahydrofuran −17.2 2816 Methyl acetate −10.0 5480 Ethyl acetate −4.05620 Dimethylcarbonate 21.7 13000  Diethylcarbonate 33.0 15000 

It is clear that the use of carbonic acid esters, in particular dimethylor diethyl carbonate, involves much lower potential risks than thoseexpected when using the solvents cited in the prior art patents.

The present invention provides remarkable advantages in the industrialprocesses for the production of Cefuroxime.

In fact, the method of the invention provides good quality Cefuroximeacid in yields quite comparable with those expected with the prior artmethods.

Moreover, the acid product can easily be converted into thecorresponding pharmaceutically acceptable salt or ester, preferably intoCefuroxime sodium salt and Cefuroxime axetil, by using conventionaltechniques known to those skilled in the art.

The process of the present invention comprises the conversion of aCefuroxime 3-hydroxymethyl or 3-hydroxymethyl-ceph-3-em precursor intothe corresponding 3-carbamoyloxymethyl derivative by reaction in asolution of the precursor at a concentration ranging from 1 to 20% byweight, with an activated isocyanate/precursor molar ratio ranging from1 to 5, wherein the activated isocyanate is preferably chlorosulfonylisocyanate, using as solvent a carbonic acid C₁-C₄ alkyl ester,preferably dimethylcarbonate, at temperatures from −40 to 20° C.,preferably from 0 to 10° C.

The progress of the carbamoylation reaction is monitored by HPLCchromatography. The reaction is over in 15÷60 minutes, when thesubstrate content in the final mixture decreases below 2% of thestarting amount.

The reaction is then quenched by addition of water or, preferably, of anacidic aqueous solution, preferably an aqueous hydrochloric acidsolution.

The product can be optionally filtered or, alternatively, recovered asthe sodium salt as described in U.S. Pat. No. 4,775,750.

The following examples illustrate the process of the invention ingreater detail.

The substrate used in the tests described in the following examples wasprepared according to the procedure described by Wilson E. M. (Chemistryand Industry 1984, 217).

EXAMPLE 1

A 1:1 solution of chlorosulfonyl isocyanate (2.4 ml) indimethylcarbonate was dropped into a suspension of(6R,7R)-7-[[2-furanyl(sin-methoxyimino)acetyl]amino]-3-hydroxymethyl-ceph-3-em-4-carboxylicacid (3.6 g) in dimethylcarbonate (35 ml) cooled to 0-4° C., under inertatmosphere, keeping the temperature below 5° C.

When the addition of the reactive was completed, the mixture was kept at0÷5° C. until the starting substrate was completely converted.

18% Hydrochloric acid (35 ml) was then added, keeping the heterogeneousmixture at a temperature ranging from 10 to 15° C. until the synthesisintermediate was completely hydrolysed.

Cefuroxime acid was recovered by filtration in the form of a whitecrystalline powder (3.8 g) in a 95% yield, or Cefuroxime sodium salt wasrecovered by the method described in U.S. Pat. No. 4,775,750 in similaryields.

The recovered product had high HPLC purity (>95%), and was characterizedby ¹H-NMR, ¹³C-NMR and mass spectroscopies, which gave the same data asthose reported in literature for Cefuroxime.

EXAMPLE 2

A 1:1 solution of chlorosulfonyl isocyanate (1.9 ml) in diethylcarbonatewas dropped into a suspension of(6R,7R)-7-[[2-furanyl(sin-methoxyimino)acetyl]amino]-3-hydroxymethyl-ceph-3-em-4-carboxylicacid (3.1 g) in diethylcarbonate (35 ml), cooled at 0° C. under inertatmosphere, until complete dissolution of the solid in solution.

When the addition of the reactive was completed, the mixture was kept at0÷5° C. for 30′, then a 18% hydrochloric acid solution (35 ml) was addedthereto.

After 90′ at temperatures ranging from 10 to 15° C., the thick whitemixture was filtered to recover Cefuroxime acid (3.1 g) in a 90% finalyield.

The NMR and Mass spectroscopical characterizations proved that therecovered product and that obtained in example 1 were identical.

EXAMPLE 3

A 1:1 solution of trichloroacetyl isocyanate (4.2 ml) indimethylcarbonate was dropped into a suspension of(6R,7R)-7-[[2-furanyl(sin-methoxyimino)acetyl]amino]-3-hydroxymethyl-ceph-3-em-4-carboxylicacid (4.5 g) in dimethylcarbonate (45 ml) cooled to 0÷4° C., under inertatmosphere, keeping the temperature below 5° C.

When the addition of the reactive was completed, the mixture was kept at0÷50C. until the starting substrate was completely converted.

Following the procedure described in U.S. Pat. No. 3,966,717, Cefuroximesodium salt was recovered in 75% yields.

In this case also, the recovered product was characterized by ¹H-NMR,¹³C-NMR and mass spectroscopies, obtaining the same data as thosereported in literature for Cefuroxime.

EXAMPLE 4

A 1:1 solution of dichlorophosphinyl isocyanate (2.5 ml) (prepared withthe method described in U.S. Pat. No. 3,314,848) in diethylcarbonate wasdropped into a suspension of(6R,7R)-7-[[2-furanyl(sin-methoxyimino)acetyl]amino]-3-hydroxymethyl-ceph-3-em-4-carboxylicacid (6.7 g) in diethylcarbonate (80 ml), cooled to 0÷4° C., under inertatmosphere, keeping temperature below 5° C.

When the addition of the reactive was completed, the mixture was kept at0÷5° C. until the starting substrate was completely converted.

Following the procedure described in U.S. Pat. No. 4,284,767, Cefuroximeacid was recovered in 70% yields.

In this case also, the recovered product was characterized by ¹H-NMR,¹³C-NMR and mass spectroscopies, obtaining the same data as thosereported in literature for Cefuroxime.

What is claimed is:
 1. A process for the preparation of Cefuroxime acidor a corresponding pharmaceutically acceptable salt or ester whichcomprises the carbamoylation of(6R,7R)-7-[[2-furanyl(sin-methoxyimino)acetyl]amino]-3-hydroxymethylceph-3-em-4-carboxylicacid with an activated isocyanate, in the presence of a carbonic acidC₁-C₄ alkyl ester as solvent for said carbamoylation reaction, and theoptional formation of the salt or ester from Cefuroxime acid.
 2. Aprocess as claimed in claim 1, in which said reaction solvent isdimethylcarbonate.
 3. A process as claimed in claim 1, in which theactivated isocyanate is chlorosulfonyl isocyanate.
 4. A processaccording to claim 1, in which the(6R,7R)-7-[[2-furanyl(sin-methoxyimino)acetyl]amino]-3-hydroxymethylceph-3-em-4-carboxylicacid is present at a concentration ranging from 1 to 20% by weight andis reacted with activated isocyanate in an activatedisocyanate/precursor molar ratio ranging from 1 to 5, at temperaturesfrom −40° C. to 20° C.
 5. A process according to claim 1, in which thecarbamoylation reaction is quenched by addition of water or an acidicaqueous solution.
 6. A process as claimed in claim 5, in which saidacidic aqueous solution is a hydrochloric acid solution.
 7. A process asclaimed in claim 1, in which the product is recovered as the sodiumsalt.
 8. A process according to claim 4, wherein the temperature isbetween 0° to 10° C.